Opioid analgesics are narcotics useful for treating moderate to severe pain and also useful in the treatment of diarrhea and coughing. Morphine, a plant alkaloid, is one of the most commonly known opiate drugs. Serious drawbacks associated with the plant opiates include their extreme addictiveness and their inhibition of intestinal transit. Naturally occurring opiates, known as "enkephalins," are found in the human brain, as well as in various tissues of lower animals. Naturally occurring enkephalin is a mixture of two pentapeptides and is part of a larger class of opioid peptides known as "endorphins." A considerable amount of research has been conducted in the hopes of producing a synthetic opiate which does not have the drawbacks associated with morphine.
The mechanism of the action of such opiates has only recently begun to be understood. The key to understanding that mechanism is the opioid receptor. A receptor is that entity, on a cell, which recognizes and binds a chemical substance. An opiate receptor, therefore, recognizes and binds an opiate drug. After binding with the receptor, opioid drugs may act to initiate or block various biochemical and physiological sequences. Such initiation or blockage is often referred to as transduction.
It has been found that there are several types of receptors which are affected by opioids. The major known types of opioid receptors are the mu, delta and kappa receptors. All three receptor types appear to mediate analgesia, but differ considerably in their other pharmacological effects. For example, mu receptors additionally mediate respiratory depression and inhibit gastrointestinal transit. Kappa receptors mediate sedation. While delta receptors are believed also to produce analgesia, as above described, it is believed that they do not inhibit intestinal transit in the manner associated with mu receptors. The biological activity and binding properties of opioids are directly linked to the opioid structure.
Opioid compounds structurally capable of binding at receptor sites may have a variety of biological effects, all of which are useful in attaining a variety of pharmacological and therapeutic effects. Certain opioids, known as "agonists", inhibit certain electrically stimulated outputs of neurotransmitters in tissues containing receptors, and, for example, may inhibit electrically stimulated contractions and other responses. Morphine is an agonist and acts to inhibit transmissions associated with pain and gastrointestinal tract contractions. It is also known that other substances, known as "antagonists", prevent the action of agonists by binding to the receptor without inhibiting electrically stimulated outputs in the manner associated with agonists. Naloxone is an antagonist and acts to prevent an agonist from binding at the receptor. Additionally, some substances act as either partial agonists or partial antagonists.
Naturally occurring opioid analgesics, known as endorphins, particularly enkephalins, have been extensively studied. The research began with the isolation of naturally occurring enkephalin, which is a mixture of methionine enkephalin (H.sub.2 N-Tyr-Gly-Gly-Phe-Met-OH) and leucine enkephalin (H.sub.2 N-Tyr-Gly-Gly-Phe-Leu-OH). Subsequent to the isolation of naturally occurring enkephalin, synthetic enkephalins were produced which displayed the full spectrum of enkephalin-like opioid effects.
Before proceeding further, it is necessary to explain briefly the terminology used to describe polypeptides. Peptides are identified by amino acid sequence using established abbreviations. For example, as used herein, "Gly" stands for glycine, "Leu" stands for leucine, "Tyr" stands for tyrosine, "Pen" stands for penicillamine, "Cys" stands for cysteine, "Phe" stands for phenylalanine, "Thr" stands for threonine and "Met" stands for methionine. Polypeptide derivatives in which one or more of the amino acids has been replaced by another amino acid are often described by reference to the basic compound and the position and nature of the substitution. The position of substitution is usually identified by reference to the number of the amino acid in the sequence starting with the amino acid at the amino terminus of the peptide chain. For example, H.sub.2 N-Tyr-Gly-Gly-Phe-Pen-OH is written as ([Pen.sup.5 ]-enkephalin) signifying that penicillamine has been substituted for the leucine or methionine normally forming the fifth amino acid from the amino terminus in enkephalin. Additionally, amino acids may exist as stereoisomers in both L and D configurations.
The large scale use of synthetic enkephalins has been impractical due to various difficulties. One of the difficulties associated with enkephalins is that they are extremely unstable and their half-lives in the blood are extremely short. Secondly, enkephalin-like peptides are known not to cross the blood brain barrier easily. They are, however, known to cross the placental barrier and cannot, therefore, be used as analgesics during pregnancy and in childbirth without affecting the unborn child.
Attempts at solving these problems focused on altering the structure of the enkephalin molecule. Alterations in the enkephalin structure produce differing pharmacological effects. Each enkephalin analog has fairly selective effects on different systems. Specifically, it has been found that different enkephalin analogs bind to different opioid receptors. However, it has been difficult to study the role of each receptor type or to induce selectively the pharmacological and therapeutic effects associated with each receptor type because the enkephalin analogs, to date, have not had a high degree of selectivity for a single-receptor type.
Recently, it has been shown that a certain enkephalin analog is highly specific to the mu receptor. See Handa, B. K., Lane, A. C., Lord, J. A. H., Morgan, B. A., Rance, M. J., and Smith, C. F. C., Eur. J. Pharmacol. 70: 531-540 (1981); Kosterlitz, H. W., and Paterson, S. J., Br. J. Pharmacol. 77: 461-468 (1982); and, Gillan, M. G. C., and Kosterlitz, H. W., Br. J. Pharmacol. 73:299P (1981), all of which are specifically incorporated herein by reference. Receptor specificity has also been achieved by conformationally constraining the enkephalin peptides. Examples of such constraints include alpha or N-methylation of the peptide backbone or cyclization.
U.S. Pat. No. 4,148,786 to Sarantakis, which is specifically incorporated herein by reference, discloses a cyclic polypeptide having the following formula: ##STR2## in which R.sup.1 is hydrogen, lower alkyl, allyl, 2-isopentenyl, 3-isopentenyl, cyclopropylmethyl, cyclobutylmethyl, phenethyl or arginyl;
R.sub.2 is hydrogen or lower alkyl; PA1 R.sub.3 is hydrogen or lower alkyl; PA1 R.sub.4 is hydrogen, hydroxymethyl, carbo(lower)alkoxy, carbamyl or carboxy; and, PA1 X is hydrogen, chloro, fluoro, bromo or iodo, the linear precursors thereof or a pharmaceutically acceptable salt thereof. PA1 R.sup.3 and R.sup.4, which may be the same or different, are hydrogen, methyl, or lower alkyl having one to five carbon atoms, provided, however, that R.sup.1, R.sup.2, R.sup.3, and R.sup.4 may not all be hydrogen when both n and m are zero; PA1 R.sup.5 is hydrogen, L-tyrosine, D-tyrosine, or L-tyrosine or D-tyrosine substituted on the N.sub..alpha. -amino with 1 or 2 lower alkyl, or alkenyl groups; PA1 R.sup.6 is a substituted or unsubstituted aromatic radical; PA1 R.sup.7 is hydrogen or methyl; PA1 R.sup.8 is carboxylate, carboxamide or amino acid residue; PA1 X and Y are hydrogen or methyl; and, PA1 n and m, which may be the same or different, are 0 or 1. PA1 R.sup.3 and R.sup.4, which may be the same or different, are hydrogen, methyl, or lower alkyl having one to five carbon atoms, provided, however, that R.sup.1, R.sup.2, R.sup.3, and R.sup.4 may not all be hydrogen; PA1 R.sup.7 is hydrogen or methyl; PA1 R.sup.8 is carboxylate, carboxamide, or amino acid residue; PA1 X and Y are hydrogen or methyl; and, PA1 Z is hydrogen, nitro, fluoro, or amino. PA1 R.sup.3 and R.sup.4, which may be the same or different, are hydrogen, methyl, or lower alkyl groups having one to five carbon atoms, provided, however, that R.sup.1, R.sup.2, R.sup.3, and R.sup.4 may not all be hydrogen when both n and m are zero; PA1 R.sup.5 is hydrogen, L-tyrosine, D-tyrosine, or L-tyrosine or D-tyrosine substituted on the N.sup..alpha. -amino with 1 or 2 lower alkyl or alkenyl groups; PA1 R.sup.6 is a substituted or unsubstituted aromatic radical; PA1 R.sup.7 is hydrogen or methyl; PA1 R.sup.8 is carboxylate, carboxamide, or amino acid residue; PA1 X and Y are hydrogen or methyl; and PA1 n and m, which may be the same or different, are 0 or 1. PA1 R.sup.3 and R.sup.4, which may be the same or different, are hydrogen, methyl, or lower alkyl having one to five carbon atoms, provided, however, that R.sup.1, R.sup.2, R.sup.3, and R.sup.4 may not all be hydrogen; PA1 R.sup.7 is hydrogen or methyl; PA1 R.sup.8 is carboxylate, carboxamide, or amino acid residue; PA1 X and Y are hydrogen or methyl; and PA1 Z is hydrogen, nitro, fluoro, or amino.
The compounds disclosed by Sarantakis are said to exert an analgesic effect in warm-blooded animals when peripherally administered. However, the Sarantakis compounds are not disclosed as specific to any receptor type. Until now, few enkephalin analogs have been developed which react specifically with the delta receptor.